P992: A MODIFIED ACTIVIN RECEPTOR TYPE II LIGAND TRAP RKER-050 RESTORED ERYTHROPOIESIS IN A MOUSE MODEL OF MYELOFIBROSIS
Authors: Blake Moses, Ashlyn Wheeler, Mike Dills, Samuel Cadena, Lorena Lerner, Jasbir Seehra, Jenn Lachey
Journal: HemaSphere (2023)

Topic: 15. Myeloproliferative neoplasms - Biology & Translational Research Background: Myelofibrosis (MF) is one of several myeloproliferative neoplasms most often associated with overactive JAK/STAT signaling, resulting in ineffective hematopoiesis, inflammation, and progressive fibrosis in the bone marrow (BM). As a compensatory mechanism, extramedullary hematopoiesis is initiated in the spleen, resulting in splenomegaly. Evidence suggests that the TGF-β superfamily’s dysregulated signaling contributes to ineffective hematopoiesis and acts directly to promote fibrosis. KER-050 and its research form, RKER-050, are investigational modified activin receptor type IIA ligand traps designed to inhibit specific TGF-β superfamily ligands, including activin A, activin B, growth and differentiation factor (GDF) 8 and GDF11. Inhibition of these ligands results in an upregulation of hematopoiesis. Additionally, the KER-050 target ligands have been shown to promote fibrosis and bone resorption in preclinical studies. Therefore, by inhibiting these ligands, KER-050 could potentially rebalance the BM microenvironment, allowing restoration of hematopoiesis and alleviating extramedullary hematopoiesis and associated splenomegaly. Aims: To investigate the potential of RKER-050 to reverse ineffective hematopoiesis in MF in a hypomorphic Gata1 MF mouse model (Gata1Low; MF mice) that presents similar characteristics to human MF, including ineffective hematopoiesis, cytopenias, extramedullary hematopoiesis and bone marrow fibrosis. Methods: Using a therapeutic treatment paradigm, ten-month-old male wildtype and MF mice were treated intraperitoneally (IP) with vehicle (WT and MF+VEH, respectively) and MF mice were treated IP with RKER-050 (10 mg/kg, MF+050) twice weekly for 12 weeks. Complete blood counts were measured from peripheral blood and erythroid and myeloid progenitors were isolated from the bone marrow and spleen and characterized via flow cytometry. Results: Anemia status of MF mice was confirmed at the start of the treatment. MF mice showed a 16% reduction in hemoglobin (Hgb) compared to WT control mice. After 12 weeks of treatment, MF+VEH mice continued to exhibit a significant or trending decrease in red blood cells (RBCs; -19%), Hgb (-20%), and hematocrit (Hct; -10%) compared to WT mice. In contrast, MF+050 mice had a significant recovery of RBCs (+31%), Hgb (+24%) and Hct (+20%), compared to MF+VEH mice, demonstrating that RKER-050 reversed anemia in this advanced disease MF model. To assess the mechanism of action of RKER-050, we evaluated erythroid precursor populations in the BM. While MF+VEH mice showed a significant reduction in erythroid progenitors compared to WT mice, treatment with RKER-050 (MF+050) resulted in increases in ProE (+55%), EryB (+66%), and Reticulocytes (+46%). These data support increased BM erythropoiesis with RKER-050 treatment. In addition, we evaluated the effect of RKER-050 on thrombopoiesis. MF+VEH mice were severely thrombocytopenic and had significantly increased megakaryocyte progenitors (MkP; +591%) compared to WT mice. Although RKER-050 significantly reduced MkP (-33%; MF+050), suggesting RKER-050 may positively influence the megakaryocyte lineage, this did not translate to improvements in thrombocytopenia, and platelet counts remained similar to MF+VEH. Summary/Conclusion: These results suggest that RKER-050 may promote erythropoiesis in the BM, potentially by rebalancing the BM niche to reverse anemia in an advanced MF mouse model. Thus, KER-050 potentially represents a promising approach for patients with MF and other hematological diseases where ineffective hematopoiesis occurs. Keywords: Transforming growth factor-, Erythropoieisis, Myelofibrosis, Myeloproliferative disorder